The human IL-2 receptor and related cytokine receptor systems are being studied to clarify the T cell immune response in normal, neoplastic, and immunodeficient states. The current focus is on mechanisms of signal transduction. Following T-cell activation by antigen, the magnitude and duration of the T-cell immune response is determined by the amount of IL-2 produced, levels of receptors expressed, and time course of each event. The IL-2 receptor contains three chains, IL-2Ra, IL-2Rb, and gc. Dr. Leonard cloned IL-2Ra in 1984, his group discovered IL-2Rb in 1986, and reported in 1993 that mutation of the gc chain results in X-linked severe combined immunodeficiency (XSCID) in humans and in 1995 that mutations of the gc-associated kinase, Jak3, result in an autosomal recessive form of SCID indistinguishable from XSCID. The group evaluated the basis for T-B+NK+ SCID and found two patients with mutations in the IL7R gene. It was reported during the past year that Jak3 not only associated with gc, but also with IL-2Rb, and the regions IL-2Rb mediating its interactions with Jak1 and Jak3 were defined. Thus, both Jak1 and Jak3 associate with IL-2Rb, whereas only Jak3 associates with gc. To identify other signaling molecules recruited by gc, the yeast two-hybrid system has been used to identify interacting proteins and it was reported that calpain can associate with gc. Calcium is a calcium-activated protease that can cleave gc following T-cell activation and it was shown that calpain could negatively regulate certain gc-mediated signals. gc-deficient mice were previously generated as a model of human XSCID. During the past year, significant advances were made in establishing a gene-therapeutic approach towards correcting the defect in these mice. It was also reported that mice lacking gc expression exhibited impaired peripheral deletion of activated T cells, helping to clarify the basis for the accumulation of peripheral CD4+ T cells in these mice. Moreover, the data suggested that gc is vital for induction of Fas ligand on activated T cells. Additional IL-2 signaling pathways, including the basis for PI 3- kinase activation, were studied and it was found that both IL-2Rb and Jak1 cooperate in the recruitment of PI 3-kinase. Efforts to clarify the basis for negative regulation of the IL-2Ra system are also in progress, particularly related to the CIS family of cytokine-inducible proteins. Previously, the lab had found constitutively activated Jak-STAT pathways in HTLV-I-transformed T cells, and it was reported that these findings extended to patients with adult T-cell leukemia. Interestingly, T-cells infected with the related HTLV-II virus did not exhibit a constitutively activated Jak-STAT pathway. Overall, these studies clarify signaling pathways in normal T-cells and in SCID, and enhance our understanding of cellular transformation.